In this new application for continued support for our studies on therapeutic idiotype vaccines we focus on improving the therapeutic efficacies in tumor therapies. We will employ new combinations of chemotherapy and anti-idiotype stimulations as well as the use of adoptive transfers of Th cells recognizing regulatory idiotypes. Since we have previously observed that only one of several so-called internal image anti- idiotypes (Ab2beta) protects against tumor growth, we will develop idiotype screening methods for predicting therapeutic effects and for choosing the best anti-idiotype for therapy. This program is outlined in four major specific aims: First, we will analyze the expression idiotopes associated with the tumor- network in longitudinal studies on individual tumor mice undergoing anti- idiotype therapy. Preliminary data indicated that the expression of certain idiotopes in serum is correlated with tumor and disease survival and that these idiotopes are prognostic for the course of the tumor growth. Second, we will suppress prognostic idiotopes associated with tumor progression and stimulate those which are high in mice surviving the tumor challenge. Third, we will follow up on our observation that tumor host survival can be significantly improved with combination therapy using anti-idiotype and cyclophosphamide. Fourth, we will use T helper cell clones, recently established in our lab, which respond to anti-idiotypes with proliferation. Mice with established tumors will receive idiotype-specific cloned T cells and these T cells will be in vivo stimulated with anti-idiotype. To better understand the underlying mechanism in adoptive T helper cell therapy we will study the T- B collaboration in vitro. Eventually, adoptive T cell therapy will be combined with chemotherapy. These proposed experiments in a well defined animal tumor model are necessary to develop a rational approach for anti-idiotype therapy in cancer patients.